This invention pertains to heterocyclic carbon compounds having drug and bio-affecting properties and to their preparation and use. In particular, the invention is concerned with 5,6,7,8-tetrahydro-4-H-isoxazolo [4,5-d]- azepin-3-ol derivatives. The compounds of this invention are cerebral function enhancers useful in treatment of various dementias due to degenerative processes as well as enhancing memory and learning.
Clinical aspects of various degenerative dementias as well as the socioeconomic problems which result in affected populations are readily appreciated by those familiar with the art. Various drug treatments directed to these disorders are currently under study. Among such drugs are a class of compounds known as nootropic agents or, more commonly, cognition enhancers. Some representatives of this class of compounds are currently being evaluated clinically for treatment of patients diagnosed as having Alzheimer's disease, a serious and fairly common CNS disorder of the elderly. Chemically, these drugs are members of a class of N-substituted-2-pyrrolidinone derivatives of formula 1: ##STR1## (a) X=H, R=--CH.sub.2 CONH.sub.2 (piracetam); (b) X=OH, R=--CH.sub.2 CONH.sub.2 (oxiracetam);
(c) X=H, R=--CH.sub.2 CONHCH.sub.2 CH.sub.2 N[CH(CH.sub.3).sub.2 ].sub.2 (pramiracetam); PA1 (d) X=H, ##STR2## (aniracetam). Butler, et al., J. Med. Chem., 27, pp. 284-691 (1984), describes the properties and testing of a representative member of this class of compounds. Preliminary clinical results with these nootropic agents, exemplified by structures 1a)-d), indicate that these drugs may have some beneficial effects in the treatment of senile dementias in the elderly.
Yevich, et al., in U.S. Pat. No. 4,668,687, disclose a series of nootropic compounds of formula 2, wherein ##STR3## R.sup.2 is hydrogen, alkyl, aryl or heterocyclic; R.sup.7 is hydrogen or is combined with R.sup.9 as a fused benzo-ring; R.sup.8 is hydrogen or alkyl; and R.sup.9 is alkyl or can be combined with R.sup.8 to form a 2-pyrrolidinone, phthalimide, or isoindolone ring system. To our knowledge, the novel tetrahydroisoxazolo[4,5-d]-azepine derivatives comprising the present invention are unrelated structurally to any reported nootropic agent.
The basic heterocycle, 5,6,7,8-tetrahydro-4H-isoxalazolo[4,5-d]azepin-3-ol (also known as THAZ) was described by Krogsgaard-Larsen, et al., in Acta Chem. Scand., B28 (1974) 533-538. In receptor binding studies THAZ has been reported to antagonize both .gamma.-aminobutyric acid (GABA) and glycine binding in certain neurons, cf: P. Krogsgaard-Larsen, et al., J Neurochem. 39(5), 1319-1324 (1982); C. Braestrup, et al., ibid 47(3), 691-696 (1986).
The novel THAZ derivatives and their utility of the present invention have not been suggested in any way by prior art.